Cyclic guanosine 3',5'-monophosphate (abbreviated as cGMP hereafter) was found in urine in rats by D. F. Ashman in 1963. Till now, it has been known that cGMP is distributed broadly in tissues of many animals including human beings. cGMP is biosynthesized from guanosine triphosphate (GTP) by the action of guanylate cyclase.
cGMP has been experimentally confirmed to have various physiological activities. For example, cGMP induces the relaxation of heart muscle and of smooth muscle. Further, it is related to the formation of neuronal synapses, and it acts as a trigger of cell proliferation and it induces the proliferation of lymphocyte.
cGMP is metabolized to physiologically inactive 5'-GMP by the action of cGMP phosphodiesterase (abbreviated as cGMP-PDE hereafter).
Accordingly, the inhibition of the action of cGMP-PDE is considered to be useful for the prevention and/or treatment of diseases induced by enhancement of the metabolism of cGMP, such as hypertension, heart failure, myocardial infarction, angina, atherosclerosis, cardiac edema, pulmonary hypertension, renal insufficiency, nephrotic edema, hepatic edema, asthma, bronchitis, dementia, immunodeficiency.
On the other hand, thromboxane A2 (abbreviated as TXA2 hereafter) was found as a constituent of the arachidonate cascade, in platelets by M. Hamberg in 1975, TXA2 is biosynthesized from arachidonic acid released from cell membrane via prostaglandin G2 and prostaglandin H2, and rapidly metabolized to inactive thromboxane B2. TXA2 is known to induce platelet aggregation and to contract smooth muscle, particularly blood vessel muscle and bronchial muscle. TXA2 synthetase was isolated and purified from microsome in platelets.
Accordingly, the inhibition of TXA2 synthetase decreases the biosynthesis of TXA2, and is useful for the prevention and/or treatment of inflammation, hypertension, thrombosis, arteriosclerosis, cerebral apoplexy, asthma, myocardial infarction, cardiostenosis, cerebral infarction, etc.
It is considered that almost any disease occurs by the complex interaction of plural mechanisms. Accordingly, the inhibition of any one of the plural mechanism may not be adequate to treat a disease. A medicament inhibiting as many mechanisms as possible, which induce the disease, is considered to be effective and ideal.
Especially, it is very useful for the prevention and/or treatment of diseases induced by platelet aggregation, e.g. angina pectoris, heart failure, pulmonary hypertension and various kinds of renal diseases to have inhibitory active on both cGMP PDE and TXA2 synthetase.